Locomotor deficits induced by lumbar muscle inflammation involve spinal microglia and are independent of KCC2 expression in a mouse model of complete spinal transection.

Spinal cord injury (SCI) is associated with damage to musculoskeletal tissues of the spine. Recent findings show that pain and inflammatory processes caused by musculoskeletal injury mediate plastic changes in the spinal cord. These changes could impede the adaptive plastic changes responsible for functional recovery. The underlying mechanism remains unclear, but may involve the microglia-BDNF-KCC2 pathway, which is implicated in sensitization of dorsal horn neurons in neuropathic pain and in the regulation of spinal excitability by step-training. In the present study, we examined the effects of step-training and lumbar muscle inflammation induced by complete Freund's adjuvant (CFA) on treadmill locomotion in a mouse model of complete spinal transection. The impact on locomotor recovery of each of these interventions alone or in combination were examined in addition to changes in microglia and KCC2 expression in the dorsal and ventral horns of the sublesional spinal cord. Results show that angular motion at the hip, knee and ankle joint during locomotion were decreased by CFA injection and improved by step-training. Moreover, CFA injection enhanced the expression of the microglial marker Iba1 in both ventral and dorsal horns, with or without step-training. However, this change was not associated with a modulation of KCC2 expression, suggesting that locomotor deficits induced by inflammation are independent of KCC2 expression in the sublesional spinal cord. These results indicate that musculoskeletal injury hinders locomotor recovery after SCI and that microglia is involved in this effect.

Gait Adaptation to a Phase-Specific Nociceptive Electrical Stimulation Applied at the Ankle: A Model to Study Musculoskeletal-Like Pain.

Introduction: Lower limb pain, whether induced experimentally or as a result of a musculoskeletal injury, can impair motor control, leading to gait adaptations such as increased muscle stiffness or modified load distribution around joints. These adaptations may initially reduce pain but can also lead to longer-term maladaptive plasticity and to the development of chronic pain. In humans, many current experimental musculoskeletal-like pain models are invasive, and most don't accurately reproduce the movement-related characteristics of musculoskeletal pain. The main objective of this study was to measure pain adaptation strategies during gait of a musculoskeletal-like experimental pain protocol induced by phase-specific, non-invasive electrical stimulation. Methods: Sixteen healthy participants walked on a treadmill at 4 km/h for three consecutive periods (BASELINE, PAIN, and POST-PAIN). Painful electrical stimulations were delivered at heel strike for the duration of heel contact (HC) using electrodes placed around the right lateral malleolus to mimic ankle sprains. Gait adaptations were quantified bilaterally using instrumented pressure-sensitive insoles. One-way ANOVAs and group time course analyses were performed to characterize the impact of electrical stimulation on heel and forefoot contact pressure and contact duration. Results: During the first few painful strides, peak HC pressure decreased on the painful side (8.6 ± 1.0%, p < 0.0001) and increased on the non-stimulated side (11.9 ± 0.9%, p < 0.0001) while HC duration was significantly reduced bilaterally (painful: 12.1 ± 0.9%, p < 0.0001; non-stimulated: 4.8 ± 0.8%, p < 0.0001). No clinically meaningful modifications were observed for the forefoot. One minute after the onset of painful stimulation, perceived pain levels stabilized and peak HC pressure remained significantly decreased on the painful side, while the other gait adaptations returned to pre-stimulation values. Discussion: These results demonstrate that a non-invasive, phase-specific pain can produce a stable painful gait pattern. Therefore, this protocol will be useful to study musculoskeletal pain locomotor adaptation strategies under controlled conditions.

H-reflex disinhibition by lumbar muscle inflammation in a mouse model of spinal cord injury.

Inflammation is a common comorbidity in patients with traumatic spinal cord injury (SCI). Recent reports indicate that inflammation hinders functional recovery in animal models of SCI. However, the spinal mechanisms underlying this alteration are currently unknown. Considering that spinal plasticity is a therapeutic target in patients and animal models of SCI, these mechanisms remain to be clarified. Using injections of complete Freund's adjuvant (CFA) in lumbar muscles as a model of persistent inflammation, the objective of this study was to assess the impact of inflammation on spinal reflex excitability after a complete midthoracic spinal transection in mice. To this end, the excitability of spinal reflexes was examined by measuring H-reflex frequency-dependent depression (FDD) on days 7, 14 and 28 following a complete spinal transection. H-reflex parameters were compared between spinal mice with CFA and control spinal mice. On day 7, lumbar muscle inflammation disinhibited the H-reflex, reflected by an attenuation of H-reflex FDD (p < 0.01), although this effect did not persist later on, either on day 14 or day 28. These results indicate that lumbar muscle inflammation alters spinal reflex excitability transiently in spinal mice. Considering that changes in spinal reflex excitability are associated with poor functional recovery after SCI, this implies that inflammation should be treated effectively to promote optimal recovery following SCI.

Functional Neuroimaging of Nociceptive and Pain-Related Activity in the Spinal Cord and Brain: Insights From Neurovascular Coupling Studies.

Spinal cord and brain processes underlie pain perception, which produces systemic cardiovascular changes. In turn, the autonomic nervous system regulates vascular function in the spinal cord and brain in order to adapt to these systemic changes, while neuronal activity induces local vascular changes. Thus, autonomic regulation and pain processes in the brain and spinal cord are tightly linked and interrelated. The objective of this topical review is to discuss work on neurovascular coupling during nociceptive processing in order to highlight supporting evidence and limitations for the use of cerebral and spinal fMRI to investigate pain mechanisms and spinal nociceptive processes. Work on functional neuroimaging of pain is presented and discussed in relation to available neurovascular coupling studies and related issues. Perspectives on future work are also discussed with an emphasis on differences between the brain and the spinal cord and on different approaches that may be useful to improve current methods, data analyses and interpretation. In summary, this review highlights the lack of data on neurovascular coupling during nociceptive stimulation and indicates that hemodynamic and BOLD responses measured with fMRI may be biased by nonspecific vascular changes. Future neuroimaging studies on nociceptive and pain-related processes would gain further understanding of neurovascular coupling in the brain and spinal cord and should take into account the effects of systemic vascular changes that may affect hemodynamic responses. Anat Rec, 301:1585-1595, 2018. © 2018 Wiley Periodicals, Inc.

Facilitation of Locomotor Spinal Networks Activity by Buspirone after a Complete Spinal Cord Lesion in Mice.

Despite efforts to potentiate spinal cord lesioned (SCL) patients' functional recovery with multi-targeted therapy combining pharmacological treatment and training, consistent improvements in locomotor control by descending transmission or spinal network facilitation are still eluding clinicians and researchers. Lately, United States Food and Drug Administration-approved buspirone has shown promise and promoted locomotor-like movement occurrence in SCL patients, but evidence on how and where it exerts its effects is lacking. The objective of the present study was, first, to verify buspirone effect on locomotor spinal network and to evaluate if it promoted functional recovery when combined with training. Also, we evaluated buspirone impact on locomotion in mice that had recovered from a previous hemisection before sustaining the spinal transection. This dual lesion paradigm has allowed confirmation of spinal network involvement in recovery after an incomplete SCL. Buspirone acutely increased the number of steps taken, the coupling strength between hindlimbs, angular excursion of the hip joint during locomotion, and improved paw positioning at contact and paw drag (ps < 0.05). Moreover, it induced long-lasting improvements of paw positioning at contact and paw drag when combined with training in mice after a dual lesion paradigm. Altogether, the results indicate that buspirone exerts considerable acute facilitation of spinally mediated locomotion, and could be used in combination with training to promote functional recovery after SCL.

Lumbar muscle inflammation alters spinally mediated locomotor recovery induced by training in a mouse model of complete spinal cord injury.

Locomotor networks after spinal cord injury (SCI) are shaped by training-activated proprioceptive and cutaneous inputs. Nociception from injured tissues may alter these changes but has largely been overlooked. The objective of the present study was to ascertain whether lumbar muscle inflammation hinders locomotion recovery in a mouse model of complete SCI. Lower limb kinematics during treadmill training was assessed before and after complete SCI at T8 (2, 7, 14, 21 and 28days post-injury). Locomotor recovery was compared in 4 groups of CD1 mice: control spinal mice; spinal mice with daily locomotor training; spinal mice with lumbar muscle inflammation (Complete Freund's Adjuvant (CFA) injection); and spinal mice with locomotor training and CFA. On day 28, H-reflex excitability and its inhibition at high-frequency stimulation (frequency-dependent depression: FDD) were compared between groups, all of which showed locomotor recovery. Recovery was enhanced by training, whereas lumbar muscle inflammation hindered these effects (knee angular excursion and paw drag: p's<0.05). In addition, lumbar muscle inflammation impaired hind limb coupling during locomotion (p<0.05) throughout recovery. Also, H-reflex disinhibition was prevented by training, with or without CFA injection (p's<0.05). Altogether, these results indicate that back muscle inflammation modulates spinally mediated locomotor recovery in mice with complete SCI, in part, by reducing adaptive changes induced by training.

Sympathetic regulation and anterior cingulate cortex volume are altered in a rat model of chronic back pain.

Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (p<0.05). In addition, intensity-dependent decreases in RBF during hind paw stimulation were attenuated by chronic pain at T2 (p's<0.05) and T10 (p's<0.05), but less so at T10 compared with T2 (p's<0.05). These results indicate that chronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system.

Neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat.

Neuroimaging methods such as functional magnetic resonance imaging (fMRI) have been used extensively to investigate pain-related cerebral mechanisms. However, these methods rely on a tight coupling of neuronal activity to hemodynamic changes. Because pain may be associated with hemodynamic changes unrelated to local neuronal activity (eg, increased mean arterial pressure [MAP]), it is essential to determine whether the neurovascular coupling is maintained during nociceptive processing. In this study, local field potentials (LFP) and cortical blood flow (CBF) changes evoked by electrical stimulation of the left hind paw were recorded concomitantly in the right primary somatosensory cortex (SI) in 15 rats. LFP, CBF, and MAP changes were examined in response to stimulus intensities ranging from 3 to 30 mA. In addition, LFP, CBF, and MAP changes evoked by a 10-mA stimulation were examined during immersion of the tail in non-nociceptive or nociceptive hot water (counter-stimulation). SI neurovascular coupling was altered for stimuli of nociceptive intensities (P<0.001). This alteration was intensity-dependent and was strongly associated with MAP changes (r=0.98, P<0.001). However, when the stimulus intensity was kept constant, SI neurovascular coupling was not significantly affected by nociceptive counter-stimulation (P=0.4), which similarly affected the amplitude of shock-evoked LFP and CBF changes. It remains to be determined whether such neurovascular uncoupling occurs in humans, and whether it also affects other regions usually activated by painful stimuli. These results should be taken into account for accurate interpretation of fMRI studies that involve nociceptive stimuli associated with MAP changes.

Changes in the flexion relaxation response induced by lumbar muscle fatigue.

BACKGROUND: The flexion relaxation phenomenon (FRP) is an interesting model to study the modulation of lumbar stability. Previous investigations have explored the effect of load, angular velocity and posture on this particular response. However, the influence of muscular fatigue on FRP parameters has not been thoroughly examined. The objective of the study is to identify the effect of erector spinae (ES) muscle fatigue and spine loading on myoelectric silence onset and cessation in healthy individuals during a flexion-extension task. METHODS: Twenty healthy subjects participated in this study and performed blocks of 3 complete trunk flexions under 4 different experimental conditions: no fatigue/no load (1), no fatigue/load (2), fatigue/no load(3), and fatigue/load (4). Fatigue was induced according to the Sorenson protocol, and electromyographic (EMG) power spectral analysis confirmed that muscular fatigue was adequate in each subject. Trunk and pelvis angles and surface EMG of the ES L2 and L5 were recorded during a flexion-extension task. Trunk flexion angle corresponding to the onset and cessation of myoelectric silence was then compared across the different experimental conditions using 2 x 2 repeated-measures ANOVA. RESULTS: Onset of myoelectric silence during the flexion motion appeared earlier after the fatigue task. Additionally, the cessation of myoelectric silence was observed later during the extension after the fatigue task. Statistical analysis also yielded a main effect of load, indicating a persistence of ES myoelectric activity in flexion during the load condition. CONCLUSION: The results of this study suggest that the presence of fatigue of the ES muscles modifies the FRP. Superficial back muscle fatigue seems to induce a shift in load-sharing towards passive stabilizing structures. The loss of muscle contribution together with or without laxity in the viscoelastic tissues may have a substantial impact on post fatigue stability.